Design, Synthesis, and Evaluation of Novel Syncarpic Acid Derivatives as Potential Anti-Inflammatory Agents.

Inflammation is a complex immune response driven by oxidative stress and proinflammatory mediators that promote tissue damage and disease progression. Although syncarpic acid exhibits antioxidant therapeutic potential, its clinical utility is limited by suboptimal efficacy and poor pharmacological properties. In the current study, we synthesized novel 4-alkyl/aryl-syncarpic acid derivatives using organocatalytic reductive C-alkylation and Rh-catalyzed α-arylation of cyclic iodonium ylides, achieving yields ranging from good to excellent. Furthermore, the antioxidant and anti-inflammatory potential of these compounds was evaluated using the DPPH radical scavenging assay, DCFDA assay, RT-qPCR, and Western blot analysis in RAW 264.7 and BEAS-2B cell lines. Our findings demonstrated that compounds 5c and 9a exhibited markedly higher antioxidant and anti-inflammatory activity compared to other syncarpic acid derivatives. Western blot analysis further revealed that compounds 5c and 9a exert their anti-inflammatory effects, at least in part, by modulating the MAPK signaling pathway. Acute toxicity studies indicate that compound 9a exhibits a favorable safety profile while retaining significant antioxidant activity. Overall, these results indicated that the syncarpic acid derivatives 5c and 9a exhibit potent anti-inflammatory efficacy and acceptable safety margins, supporting their potential therapeutic application in inflammatory disorders such as acute respiratory distress syndrome (ARDS) and ulcerative colitis.